Project Summary/Abstract Currently more than 100 million Americans and 1.5 billion people worldwide suffer from chronic pain. This is more than cancer, diabetes, and heart disease combined. Voltage-gated sodium channels are responsible for the transmission of pain signals. Nine genes have been identified, each having unique properties and tissue distribution patterns. Genetic studies have correlated a hereditary loss-of-function mutation in one human Na+ channel isoform ? ?Na?V?1.7 ? with a rare genetic disorder known as Congenital Insensitivity to Pain (CIP). Individuals with CIP are not able to feel pain without any significant secondary alteration. Thus, selective inhibition of ?Na?V?1.7 in normal humans could recapitulate the phenotype of CIP. However, the high homology of human ?Na?V proteins have frustrated most efforts to develop selective inhibitors. We have developed a non-permanent gene therapy to target pain that is non-addictive (because it targets a non-opioid pathway), highly specific (only targeting the gene of interest), and long-term lasting (around 3 weeks in preliminary assays in mice). During this Phase I SBIR, we will 1) test additional pain targets ?in vitro?, and 2) evaluate the new targets ?in vivo ?in mice models of inflammatory and neuropathic pain. In addition, we will initiate our toxicology studies in mice. At the end of this Phase I work, we will know the spectrum of activity and safety of our optimized candidate to perform IND-enabling toxicology studies in Phase II.